The contribution of CD8+ T cells in controlling HIV-1 is well recognized, and this is particularly evident during acute infection. Although we and others have identified both the relatively strong CD8+ and weak CD4+ T cell responses that occur in newly infected patients, the precise characteristics of immunity that provide optimal control and sustained lower viral setpoint are poorly defined. We propose to identify elements of the acute and evolving T cell immune response that can confer a long-term advantage in controlling HIV-1 infection. The investigation will focus on 10 acutely infected patients enrolled annually and followed longitudinally, as well as 25 others already enrolled. In Aim 1, we will assess comprehensively the initial CD8+ and CD4+ T cell responses whose epitopes span the entire genome of both reference and the earliest autologous viruses. We will identify unique features of adaptive T cell immunity in acute vs. chronic infection, and we will contrast responses recognizing conserved and variable regions identified by whole genome sequencing of various cell targets (Project 1, Mullins). In Aim 2, we will examine the phenotype and multiple anti-viral functions of the HIV-1-specific T cells. These investigations will determine the activities that confer efficient anti-viral activities in vitro and correlate with lower viral setpoint in vivo or favorable therapeutic response. In Aim 3, we will evaluate the evolution of T cell responses relative to viral diversity (Project 1, Mullins) and viral fitness (Project 3, Arts) as setpoint is established and maintained. These studies will identify the characteristics of T cell responses that lead to viral escape mutations and the effect of these mutations within T cell epitopes on replicative capacity. Our findings will provide a more complete understanding of the dynamics and the most critical anti-viral components of T cell adaptive immunity during acute infection. This knowledge will have a potentially significant impact on devising strategies and monitoring effects of early treatment. In addition, these studies will better define immune responses important to elicit in T cell based vaccines.